We propose to evaluate genetic variants at three metabolism steps in human lipoprotein metabolism for their causal relationship to premature atherosclerosis. The gene products are: 1) Lysosomal acid lipase (LAL) which hydrolyzes low density lipoprotein cholesteryl ester (LDL-CE) to free cholesterol and fatty acid. We have established that hypercholesterolemia occurs significantly more often in people who inherit a single deffective gene for LAL. These studies will establish the associated risk of developing a premature myocardial infarction. 2) Neutral cholesteryl esterase (NCE) which hydrolyzes the CE formed in microsomes by acyl CoA: cholesterol cyltransferase (ACAT) to free cholesterol and fatty acid. Our studies are designed to establish the degree of genetic variation that occurs at this locus and the associated risk, if any, of premature atherosclerosis. 3) Apolipoprotein E (apoE). A genetic polymorphism exist at the locus for apoE (Epsilon). Three alleles exist with gene frequencies of EpsilonII=11%, EpsilonIII=72%, EpsilonIV=17%. The genotype EpsilonIV/EpsilonIV occurs in 1-3% of the population of which 5% will manifest type III hyperlipoproteinemia. Thus far, all people with type III hyperlipoproteinemia are genotype EpsilonIV/EpsilonIV. Our studies are designed to: (a) establish whether individuals with genotype EpsilonIV/EpsilonIV have a reduced rate of chylomicron remnant clearance, and if so, whether heterozygotes for EpsilonIV (EpsilonII/EpsilonIV, EpsilonIII/EpsilonIV) also have impaired clearance of chylomicron remnants; (b) establish whether individuals with genotype EpsilonIV/EpsilonIV have an associated risk for premature coronary and/or peripheral vascular disease and if so, is there a risk associated with being heterozygous for EpsilonIV (EpsilonII/EpsilonIV, EpsilonIII/EpsilonIV); (c) establish what associated single gene defects contribute to the manifestation of type III hyperlipoproteinemia in individuals with the genotype EpsilonIV/EpsilonIV.